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Integrated genomics point to immune vulnerabilities in pleural mesothelioma

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Nastase, Anca 
Mandal, Amit 
Lu, Shir Kiong 
Anbunathan, Hima 
Morris-Rosendahl, Deborah 


Abstract: Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.


Funder: Libor Fund grant from the UK Department of Health, by the British Lung Foundation and by the Asmarley Foundation

Funder: UK Medical Research Council


Article, /631/67, /631/114, /631/250, /631/337, /692/53, /692/308, /692/4028, article

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Scientific Reports

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Nature Publishing Group UK